Energy (DOE) Office of Science User Facility operated for the DOEOffice of Science by Argonne National Laboratory under contractno. DE-AC02-06CH11357. Use of the Center for NanoscaleMaterials, a DOE Office of Science User Facility, was supportedby the DOE Office of Science, Office of Basic Energy Sciences,under contract no. DE-AC02-06CH11357. This research usedresources of the National Energy Research Scientific ComputingCenter, which is supported by the DOE Office of Science undercontract no. DE-AC02-05CH11231. An award of computer time wasprovided by the Innovative and Novel Computational Impact onTheory and Experiment (INCITE) program. This research usedresources of the Argonne Leadership Computing Facility atArgonne National Laboratory, which is supported by the DOEOffice of Science under contract no. DE-AC02-06CH11357. All dataare reported in the main text and supplementary materials. Y.S.initiated and led the project. X.Z., Y.S., and S.P. carried outthe experiments. X.Z. and Y.S. analyzed the experimental data.

S.K.R.S.S. directed the MD simulations. B.N., G.K., and S.K.R.S.S.
carried out and analyzed the MD simulations. Y.S. wrote the
manuscript with input from all the authors.

The African naked mole-rat’s (Heterocephalus glaber) social and subterranean lifestyle
generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours
of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without
apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism
fueled by fructose, which is actively accumulated and metabolized to lactate in the brain.

Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase
were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic
respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via
phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can
circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be
harnessed to minimize hypoxic damage in human disease.

In all kingdoms of life, extreme habitats drive adaptive change to enable species to exploit challenging environments. One challenge faced by subterranean mammals that inhabit con- fined spaces is an atmosphere low in O2 andhigh in CO2. We studied the naked mole-rat’s(Heterocephalus glaber) adaptation to low-O2 andhigh-CO2 conditions (Fig. 1A), as this eusocial ro-dent combines a subterranean lifestyle with largecolony sizes of up to 280 members (1–3). CO2levels in naked mole-rat burrows can reach 7 to

10%, orders of magnitude higher than in surface
air (4). Correspondingly, naked mole-rats do not
begin to display behavioral avoidance, hyperventilation, or tissue acidosis until CO2 levels reach
10% (fig. S1, A to E). Even a 5-hour exposure to
80% CO2 (20% O2) was not lethal for naked mole-rats (fig. S1F). O2 levels are low in the burrows of
subterranean mammals (as low as 6%) (5, 6), and
the mass huddling behavior of naked mole-rats
may exacerbate their exposure to hypoxic stress.

To investigate the molecular mechanisms that
allow naked mole-rats to overcome hypoxic stress,
we subjected them to controlled hypoxia using
atmospheric chambers (Fig. 1, B and C), as approved by local ethics committees. Naked mole-rats tolerated a chronic hypoxic environment of
5% O2 for 5 hours with no apparent ill effects,
whereas mice (Mus musculus) died in less than
15 min (Fig. 1B). We next exposed animals to 0% O2
in a chamber flushed with N2 (10 liters/min).

(7) to a steady 50 bpm throughout anoxia (Fig.
1E). In mice, the heart rate rapidly and continuously declined until ~6 min, when it was undetectable by electrocardiogram (Fig. 1E). In anoxic
conditions, circulating hemoglobin, which shows
a high affinity for O2 (8), could provide a minimal
O2 supply to naked mole-rat organs. During anoxia, naked mole-rat body temperature was maintained at 30°C (fig. S3B), the preferred body
temperature of these poikilothermic animals (9, 10).
However, warming naked mole-rats to 37°C decreased maximum survival times to 6 min, still
much longer than mouse survival times (fig. S3C).

Experiments with isolated hearts (
Langen-dorff preparation) exposed to hypoxia (by stopping
perfusion with oxygenated buffer for 30 min)
showed that left ventricular developed pressure
(LVDP) recovered almost completely to pre-ischemic
values in naked mole-rats but not in mice (Fig.
1G and table S1). The mouse LVDP never recovered to more than 65% of baseline, even when
examined at 30°C. Thus, the ability of the naked
mole-rat heart to continue beating under anoxia
is supported by an intrinsic cardiac hypoxia resistance. Both hypercapnia and hypoxia lead to
pulmonary edema in mice but not in naked mole-rats (fig. S4, A and B).

We postulated that naked mole-rat vital organs
survive O2 deprivation with metabolic suppression similar to hibernation, torpor, or suspended
animation–like states (11–13). Using metabolomics
based on gas chromatography–mass spectrometry
(GC-MS) (14, 15), we measured quantitative changes
in metabolite concentration during anoxia (
calibrations in fig. S5) and compared normoxic baseline values to those at 40 s and 10 min (mouse)

1Laboratory of Integrative Neuroscience, Department of
Biological Sciences, University of Illinois at Chicago, Chicago,
IL 60607, USA. 2Molecular Physiology of Somatic Sensation,
Max Delbrück Center for Molecular Medicine, Berlin,
Germany. 3Department of Zoology and Entomology,
University of Pretoria, Pretoria, Republic of South Africa.